Chemical Hazards: How Do We Translate Presence to Risk? An Overview of Risk Analysis

James R. Coughlin, PhD CFSPresident, Coughlin & Associates

Aliso Viejo, Californiajrcoughlin@cox.net

www.linkedin.com/in/jamescoughlin

IAFP / Charlotte / July 29, 2013SYMPOSIUM

“Chemical Risk Assessment 101: A Better Understanding of a Complex

Subject Made Easier”

Objectives/Outline

Why is toxicology and risk assessment of chemicals important for foods and food ingredients?

General toxicology considerations, toxicity evaluation and risk assessment

Key determinants of human risk Consider “Risk-Benefit” Evaluation:

Acrylamide as case example California Proposition 65

Paracelsus (1493-1541)

THE basic tenet of all Toxicology:

“The dose alone makes the poison.”

Toxicology – A Multidisciplinary Science

Chemistry Biology Pathology Physiology New Fields: Genomics Proteomics Toxicogenomics Nutrigenomics

Nutrition Immunology Public Health Pharmacology Statistics Epidemiology Newest:

The Microbiome

Acute / Chronic Exposure and Health Effects

“Acute” ExposureA single exposure to a chemical that can result in some form of toxicity or illness

“Chronic” ExposureUsually a lower-dose exposurefor longer periods of time, associated with chronic/delayed effects

Factors That Influence Toxicity Dose / duration / frequency of intake Species / strain / age / sex General state of health Genetic & epigenetic factors Nutritional status Individual susceptibility (child, pregnant

woman, elderly, immune compromised) Synergism / antagonism Adaptation to the effect

Fate of Toxicants in Living Systems“ADME”

Absorption - how much is absorbed by the body?

Distribution - what organs/body fluids does the toxicant go to?

Metabolism - is it modified by enzymes in the body, and to what extent? Activation to more toxic compound vs. Detoxification

Excretion - how much of the toxicant (or its metabolites) is retained and/or removed from the body?

Specialized Toxicity Tests1. Reproductive (multigeneration)

2. Teratogenicity (birth & developmental)

3. Mutagenicity (short-term, in vitro & in vivo)

4. Neurobehavioral

5. Immuno-toxicological

6. Endocrine effects

7. Potentiation / Promotion

8. Carcinogen Bioassays

Human Relevance of Rodent Cancer Bioassays

Some eminent toxicologists have questioned the human relevance of tumors seen in lifetime rodent bioassays, and they believe it’s time to STOP doing chronic rodent bioassays at the “Maximum Tolerated Dose”

We toxicologists make two possibly flawed assumptions about chronic cancer bioassays… Dose Extrapolation – effects seen at high rodent doses will also

occur at much lower human doses Species Extrapolation – if cancer is seen in rodents, then cancer

probably occurs in humans

BUT…we need to understand Mechanisms and Modes of Action for a chemical before we can use bioassay tumor results for regulatory or warning purposes.

Risk Assessment Paradigm Hazard Identification - Determination of adverse effects

caused by high intakes of the chemical (epidemiology, clinical, animal, short-term and specialized studies)

Dose-Response Assessment Selection of critical data set and toxic effect levels Determination of Uncertainty or Safety Factors Derive an Acceptable Daily Intake (ADI)

Exposure (Intake) Assessment Evaluation of the range and distribution of human intakes

Risk Characterization Estimation of the fraction of the population exceeding ADI Evaluation of the magnitude of potential excess intakes.

Methods for Oral “RfDs” RfDs - U.S. EPA’s Reference Dose (similar to other agencies’

Acceptable Daily Intake or “ADI”)

NOAEL - “No Observed Adverse Effect Level” – dose found experimentally where there is an absence of adverse effects

LOAEL - “Lowest Observed Adverse Effect Level” – the lowestexperimental dose which increases the frequency or severity of toxic effects

Uncertainty Factors - in risk assessment of chemical toxicants, generally 10-fold increments with 100-fold as the default

Modifying Factors - magnitude depends on study weaknesses, severity of effects, bioavailability, susceptible subpopulations (such as diseased people, kids).

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Acrylamide Snapshot: Chemistry and Toxicology

Occupational neurotoxin; genotoxic / mutagenic in cell cultures

Known rat carcinogen, classified as “probable human carcinogen”

Metabolized to glycidamide (an epoxide), also an animal carcinogen

Acrylamide & glycidamide can bind to DNA, amino acids and proteins

DNA adducts carcinogenic potential

Blood hemoglobin adducts biomarker of exposure

Dietary proteins may reduce acrylamide uptake in humans

Protective enzymes can detoxify acrylamide and glycidamide

Discovered by the Swedes in 2002 in hundreds of heat-processed

food products, making up about 40% of our calories.

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Swedish Discovery of Acrylamide in Foods(announced April 2002)

Tareke et al., J. Agric. Food Chem. 50: 4998-5006 (2002)

Discovered after illness investigations of tunnel workers exposed to acrylamide as a grouting agent in 1997; background levels of Hemoglobin-acrylamide adducts of non-smoking Swedes were found to be elevated

Higher temperature / time / surface area increase levels: Carbohydrate-rich foods high: 150 - 4,000 ppb Protein-rich foods low, e.g. meats: 5 - 50 ppb Not detected in unheated or boiled foods; 120 C is needed

Swedish adult acrylamide intake estimated to be 100 μg/day, but now known to be much lower in most populations.

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AmmoniaAlkyl aminesAmino acidsProteinsPhospholipids

AldehydesKetonesSugarsCarbohydratesLipids

CarbonylsEstersAmides (Acrylamide)Heterocyclic Compounds

Amine

Carbonyl

Amino-CarbonylInteraction

(Amadori Products)

HEATHEAT

Furans OxazolesPyrroles ImidazolesThiophenes PyridinesThiazoles Pyrazines

Melanoidins(pigments)

Volatile Compounds(aroma chemicals)

General Scheme of Maillard Browning Reaction

Food Acrylamide Range (ppb)Baby food/biscuits ND - 442

Breads/bakery products ND - 364

Cereals 11 - 1057

Chocolate products ND - 909

Coffee (roasted, not brewed) 37 - 374

Coffee (brewed) 5 - 11

Cookies/crackers 26 - 1540

Dairy drinks ND - 43

Dried foods/mixes ND - 1184

Food Acrylamide Range (ppb)French fries 117 - 1325

Fruits/vegetables (canned) ND - 83

Gravies/seasonings ND - 151

Infant formulas ND

Nuts/nut butters ND - 457

Potato chips 117 - 4080

Snacks (other salty) 12 - 1340

Olives 123 - 1925

Prune juice 53 - 326

U.S. National Toxicology Program (NTP) –Carcinogen Bioassay of Acrylamide

U.S. FDA nominated acrylamide and glycidamide for complete toxicology testing in November 2002 for future risk assessment purposes

2-year cancer bioassay in rats and mice fed acrylamide in drinking water(untreated control + 4 treatment doses), with ancillary studies on metabolism, genotoxicity and toxicokinetics

NTP Technical Report No. 575 was peer-reviewed in April 2011; Panel accepted conclusions that there was “Clear Evidence of Carcinogenicity” in male & female rats and male & female mice

For consideration: the observed NTP tumor findings and cancer potencies may be useful in increasing acrylamide’s acceptable risk level.

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Acrylamide Risk Assessment Considerations Based on NTP Cancer Bioassay

FAO/WHO Joint Expert Committee on Food Additives (JECFA) acrylamide risk assessment (2010) used preliminary NTP data on benign tumors in the rat mammary gland and mouse Harderian gland, but these endpoints are not biologically relevant to human risk assessment

JECFA and national authorities should reevaluate acrylamide’s potential for human risk based on the lower incidences of more relevant NTP malignant rat and mouse tumor endpoints

Lack of human cancer risk must be factored into any risk assessment and risk management plans adopted by national regulatory agencies (FDA, Health Canada, EFSA) and global public health authorities (JECFA, Codex).

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Recent Dietary Epidemiology Studies of Acrylamide (Human Studies)

Pelucchi et al. 2011. “Exposure to Acrylamide and Human Cancer - A Review and Meta-analysis of Epidemiologic Studies.” Annals Oncology 22: 1487-1499. “Conclusions: Available studies consistently suggest

a lack of an increased risk of most types of cancer from exposure to acrylamide.”

Lipworth et al. 2012. “Review of Epidemiologic Studies of Dietary Acrylamide Intake and the Risk of Cancer.” Eur. J. Cancer Protection 21: 375-386.Concluded no increased human risk, and urged that

no further epidemiology studies even be initiated.

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“Acrylamide in Foods: A Review of the Science andFuture Considerations”

David R. Lineback, James R. Coughlin and Richard H. Stadler,Ann. Rev. Food Sci. & Technol. 3: 15-35 (April 2012)

Most countries have advised consumers to follow the dietary recommendations for a balanced diet issued by their food regulatory and public health agencies.

The data available to date have been insufficient to warrant any recommendation for a significant change in the dietary recommendations because of acrylamide.

Current epidemiological and toxicological evidence are insufficient to indicate that the amounts of acrylamide consumed in the normal diet are likely to result in adverse human health effects, particularly cancer.

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No Significant Risk Level [NSRL] = (1 x 10-5)

Over 500 Carcinogens

MADL = No Observable Effect Level1000

Over 300 Reproductive Toxicants [DARTs]

Exposure (µg/day), Not Concentration!

Acrylamide Battleground under California Prop 65 Listed in 1990 as a carcinogen; “Safe Harbor” level = 0.2 μg/day; must

stay below this level to avoid cancer warnings; if you can detect it, even a 1-ounce serving of any food exceeds this level

French fries: Attorney General sued and settled case (2008) against frozen fries/tater tots demanding a 50% reduction in levels; fast-food restaurant fries have had cancer warnings posted for years

Potato chips: AG settled (2008) the case against chip manufacturers; agreement to cut levels to 275 ppb by end of 2011 (20 - 85% reductions) to avoid warnings; no warnings currently being given

Cereals: Private “bounty hunter” lawyers sued cereal manufacturers in 2009; case is still pending

Coffee: “Bounty Hunter” sued coffee shops in 2010 over brewed coffee; 10 x 10-inch cancer warning placards have been posted; another case now in court against over 120 coffee roasters for packaged roast coffees.

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Benefit-Risk Evaluation –

The “Holistic Approach”

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Food and Chemical Safety Issues We usually test individual food chemicals, not the whole

foods or beverages (except with epidemiology) For whole foods, we must identify biologically active toxic

component(s) Must determine appropriate mechanism of action of

specific chemicals (carcinogens, reproductive toxicants) Key importance of dose-response relationships Interactions with diet/nutrients, environment & drugs Explore sensitive segments of population (young, aged)

Risk/Benefit Assessment is crucial need: Goal: NO “significant or unreasonable” risk!!

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“Benefit-Risk Evaluation” to Assess the Safety of Foods Containing Toxicants and Carcinogens

I believe we’ve been doing it the WRONG WAY for decades, by simply evaluating the risk of individualchemicals one by one in a food

Going forward, I believe the RIGHT WAY is to evaluate the safety of the whole food by comparing its risks vs. benefits using the “Holistic Approach”

Various “Benefit-Risk Evaluations” and regulatory guidance documents have recently been published in the U.S. [FDA’s “Mercury in Fish” evaluation] and Europe [EFSA, ILSI Europe].

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